TBX15 increases ferroptosis to overcome sorafenib resistance via HERC5-mediated cGAS ISGylation in hepatocellular carcinoma.

The drug resistance to targeted therapy in patients with advanced hepatocellular carcinoma (HCC) is gradually increasing. Thus, it is very important to further examine the molecular signaling pathways related to HCC and the corresponding targeted therapy. The study identified a significant association between low TBX15 expression and sorafenib resistance in HCC. TBX15 increased sorafenib sensitivity in HCC cells by inducing ferroptosis in vivo and vitro experiments. Mechanistically, TBX15 promoted the secretion of mitochondrial DNA (mtDNA) into the cytoplasm through the opening of the mitochondrial permeability transition pore, then stimulated the cGAS/STING pathway due to the increased cytosolic mtDNA. TBX15 binds to the HERC5 promoter region, increasing cGAS ISGylation and enhancing its stability. Furthermore, the activation of cGAS/STING pathway increased ferroptosis in HCC cells. Our research underscores TBX15's potential to counteract sorafenib resistance and establishes the TBX15-cGAS/STING axis as a key regulator in HCC pathobiology.